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Modulation of Alzheimer-like synaptic and cholinergic deficits in transgenic mice by human apolipoprotein E depends on isoform, aging, and overexpression of amyloid β peptides but not on plaque formation
Open accessAbstract
The most frequent human apolipoprotein (apo) E isoforms, E3 and E4, differentially affect Alzheimer's disease (AD) risk (E4 > E3) and age of onset (E4 < E3). Compared with apoE3, apoE4 promotes the cerebral deposition of amyloid beta (Abeta) peptides, which are derived from the amyloid precursor protein (APP) and play a central role in AD. However, it is uncertain whether Abeta deposition into plaques is the main mechanism by which apoE isoforms affect AD. We analyzed murine apoE-deficient transgenic mice expressing in their brains human APP (hAPP) and Abeta together with apoE3 or apoE4. Because cognitive decline in AD correlates better with decreases in synaptophysin-immunoreactive presynaptic terminals, choline acetyltransferase (ChAT) activity, and ChAT-positive fibers than with plaque load, we compared these parameters in hAPP/apoE3 and hAPP/apoE4 mice and singly transgenic controls at 6-7, 12-15, and 19-24 months of age. Brain aging in the context of high levels of nondeposited human Abeta resulted in progressive synaptic/cholinergic deficits. ApoE3 delayed the synaptic deficits until old age, whereas apoE4 was not protective at any of the ages analyzed. Old hAPP/apoE4 mice had more plaques than old hAPP/apoE3 mice, but synaptic/cholinergic deficits preceded plaque formation in hAPP/apoE4 mice. Moreover, despite their different plaque loads, old hAPP/apoE4 and hAPP/apoE3 mice had comparable synaptic/cholinergic deficits, and these deficits were found not only in the hippocampus but also in the neocortex, which in most mice contained no plaques. Thus, apoE3, but not apoE4, delays age- and Abeta-dependent synaptic deficits through a plaque-independent mechanism. This difference could contribute to the differential effects of apoE isoforms on the risk and onset of AD.
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“Introduction of human APOE to existing FAD-Tg mice significantly delays plaque deposition, although once detected, plaque levels are generally greater with APOE4 than APOE3 (3, 6 -8).”
From APOE4-specific Changes in Aβ Accumulation in a New Transgenic Mouse Model of Alzheimer Disease (2012) · cites this paper as [6]
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“ApoE has a major impact on the generation of amyloid deposits in the AD mouse brain and deletion of ApoE in most AD mouse models significantly inhibits amyloid plaque formation [6], [7], [8].”
From Lack of LDL receptor enhances amyloid deposition and decreases glial response in an Alzheimer's disease mouse model (2011) · cites this paper as [6]
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“Other studies using transgenic mice that possess different human apoE transgenes also demonstrate an isoform-specific difference (E4>E3) in Aβ deposition (Buttini et al., 2002; Dolev and Michaelson, 2004).”
From The role of apolipoprotein E in Alzheimer's disease (2009) · cites this paper as Buttini et al., 2002
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“APP transgenic mice deficient for ApoE show a dramatic decrease in fibrillary amyloid deposits [5], [6], [7], [8], [9].”
From Lack of LDL receptor enhances amyloid deposition and decreases glial response in an Alzheimer's disease mouse model (2011) · cites this paper as [6]
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Mauch, D. H., Nägler, K., Schumacher, S., Göritz, C., Müller, E.-C., Otto, A., & Pfrieger, F. W. (2001) · Science · doi:10.1126/science.294.5545.1354 · Cited by 1,711 · cited 1×
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Background
Research works printed but not linked: 1
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Items 101–183 of 183
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“In mammals choline metabolism has been linked to Alzheimer’s disease (AD) [32,33].”
BackgroundEffect of human apolipoprotein E genotype on the pathogenesis of experimental ocular HSV-1
Bhattacharjee, P. S., Neumann, D. M., Foster, T. P., Bouhanik, S., Clément, C., Vinay, D. S., Thompson, H. W., & Hill, J. M. (2008) · Experimental Eye Research · doi:10.1016/j.exer.2008.05.007 · Cited by 40
“Transgenic mouse model studies of homozygous or heterozygous human apoE isoforms suggest that apoE4 is not only less neuroprotective but also acts as a dominant negative factor, retarding the beneficial effects of apoE3 (Buttini et al., 2002).”
BackgroundShah, D., Blockx, I., Guns, P., Deyn, P. P. D., Dam, D. V., Jonckers, E., y Palacios, R. D., Verhoye, M., & der Linden, A. V. (2015) · NeuroImage · doi:10.1016/j.neuroimage.2015.01.009 · Cited by 39
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BackgroundAdvances on the Understanding of the Origins of Synaptic Pathology in AD
Lacor, P. N. (2007) · Current Genomics · doi:10.2174/138920207783769530 · Cited by 40
“Such impairment of synaptic plasticity may also account for plaque-independent cognitive failure seen in hAPP-Tg mice [152,192,237,238], which accumulate soluble oligomers as mentioned above [120].”
BackgroundIn situ AFM studies of astrocyte-secreted apolipoprotein E- and J-containing lipoproteins
Legleiter, J. A., Demattos, R. B., Holtzman, D. M., & Kowalewski, T. (2004) · Journal of Colloid and Interface Science · doi:10.1016/j.jcis.2004.05.009 · Cited by 38
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Mouse Models of Human Neurodegenerative Disorders
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“the amyloid precursor protein (APP), have been achieved, alone or in combination with known mutations in other familial forms, including presenilin and tau (Table).(1-6) Each of the mutated APPs shows amino acid substitutions around the proteolytic cleavage sites of the or secretases.”
BackgroundHackett, T. A., Clause, A. R., Takahata, T., Hackett, N., & Polley, D. B. (2015) · Brain Structure and Function · doi:10.1007/s00429-015-1062-3 · Cited by 35
“…blocking solution (Superblock, ScyTek Laboratories, Logan, UT, USA), followed by a single rinse in PBS. Superblock reagent reduces nonspecific antibody binding and was used in lieu of species-specific sera or bovine serum albumin (Buttini et al. 2002; Evans et al. 1996; Turtzo et al. 2014).”
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Diet and Age Interactions with Regards to Cholesterol Regulation and Brain Pathogenesis
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“Other studies using transgenic mice that possess different human ApoE transgenes have also demonstrated that Aβ deposition occurs in an isoform-dependent manner (E4 > E3) [112, 113].”
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“…of varying severity have been described, depending on mouse type and age (Wong et al., 1999; Bronfman et al., 2000; Diez et al., 2000; Jaffar et al., 2001; Hernandez et al., 2001; Boncristiano et al., 2002; Buttini et al., 2002; German et al., 2003; Klingner et al., 2003; Luth et al., 2003).”
Esposito, L., Gan, L., Yu, G.-Q., Essrich, C., & Mucke, L. (2004) · Journal of Neurochemistry · doi:10.1111/j.1471-4159.2004.02816.x · Cited by 33
“…to what extent extracellular amyloid deposits contribute to loss of neuronal viability or function in AD and related experimental models (Blennow et al. 1996; Sloane et al. 1997; Lambert et al. 1998; Chui et al. 1999; Hsia et al. 1999; Mucke et al. 2000; Buttini et al. 2002; Westerman et al. 2002).”
BackgroundApolipoprotein E and the Risk of Breast Cancer in African-American and Non-Hispanic White Women
Moore, R. J., Chamberlain, R. M., & Khuri, F. R. (2004) · Oncology · doi:10.1159/000077433 · Cited by 29
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Acetylcholine receptor and behavioral deficits in mice lacking apolipoprotein E
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“Mice lacking apoE (Apoe−/−) show decreased cholinergic functioning compared to wild type (Apoe+/+) mice (Buttini et al., 2002; Chapman and Michaelson, 1998; Gordon et al., 1995; Kleifeld et al., 1998).”
BackgroundApoE4 Induces Synaptic and ERG Impairments in the Retina of Young Targeted Replacement ApoE4 Mice
Antes, R., Ezra-Elia, R., Weinberger, D., Solomon, A., Ofri, R., & Michaelson, D. M. (2013) · PLoS ONE · doi:10.1371/journal.pone.0064949 · Cited by 29
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“earlier time point than those expressing apoE3 [12,13].”
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Intracerebroventricular passive immunization with anti‐oligoAβ antibody in TgCRND8
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“of studies, including our own, have substantiated this fact in the animal models of AD showing destructive potential of oligomeric Ab involved in plaque-independent synaptic degeneration (Mucke et al., 2000; Chauhan and Siegel, 2002; Buttini et al., 2002; Van Dam et al., 2003; Palop et al., 2005), impairment in learni…”
BackgroundResultInfluentialChoi, J. G., Moon, M., Kim, H. G., Mook‐Jung, I., Chung, S.-Y., Kang, T. H., Kim, S. Y., Lee, E. H., & Oh, M. S. (2011) · Neurobiology of Learning and Memory · doi:10.1016/j.nlm.2011.06.004 · Cited by 24
“It is known that AbO induces deficits in both synaptic and cholinergic neurons in an AD mouse model (Buttini et al., 2002).”
Lloyd, G. M., Trejo‐Lopez, J. A., Xia, Y., McFarland, K. N., Lincoln, S., Ertekin‐Taner, N., Giasson, B. I., Yachnis, A. T., & Prokop, S. (2020) · Acta Neuropathologica Communications · doi:10.1186/s40478-020-0891-3 · Cited by 24
“The ε3 allele is associated with preservation of synaptic integrity in old human APP (hAPP) mice [7], and mediation of amyloid clearance in comparison to ε4 [5], but it was also correlated to an earlier age of onset than ε4 in this model [7, 30].”
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“…however, have shown that significant neuronal death does not occur in most areas of the aging nervous system, and, therefore, cannot explain age-related functional changes (Kemper, 1993; Peters et al., 1994, 2001; Geinisman et al., 1995; Morrison and Hof, 1997; Masliah, 2001; Buttini et al., 2002).”
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“Remarkably, decreased levels of choline acetyltransferase have also been reported in apoE4 mice (Buttini et al. 2002) while the exposure to the pesticide chlorpyrifos, a cholinesterase inhibitor, impaired memory in apoE3 mice but not in apoE4 mice (Peris-Sampedro et al. 2015).”
BackgroundRescuing neurons in prion disease
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“…blocking solution (Superblock, ScyTek Laboratories, Logan, UT), followed by a single rinse in PBS. Superblock reagent reduces nonspecific antibody binding, and was used in lieu of species-specific sera or bovine serum albumin (Evans et al., 1996; Buttini et al., 2002; Turtzo et al., 2014).”
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“Moreover, synaptic and dendritic alterations and significant learning deficits, all of which have been associated with local neurite remodeling, are observed in ApoEdeficient mice [140] and ApoE4 transgenic mice [141–146].”
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“[28,34] +”
CSF cutoffs for MCI due to AD depend on APOEε4 carrier status
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“Moreover, APOEε4 seems to have a detrimental role in neuronal repair and remodelling during stress or injury (Bu, 2009), synaptic plasticity (Buttini et al., 2002), neurogenesis (Andrews-Zwilling et al., 2010), and neuroinflammation (Ringman et al., 2012).”
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Peptide-Liganded G Protein-Coupled Receptors as Neurotherapeutics
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“In fact, synapse loss does occur in certain hAPP tg mouse AD models (Hsia et al., 1999), including an AD-like degeneration of the cholinergic phenotype (Buttini et al., 2002).”
BackgroundHolden, S. J., Kundu, P., Torres, E. R. S., Sudhakar, R., Krenik, D., Grygoryev, D., Turker, M. S., & Raber, J. (2022) · Frontiers in Aging Neuroscience · doi:10.3389/fnagi.2022.767558 · Cited by 10
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“By way of contrast, ApoE2 and ApoE3 protect neurons against excitotoxic stress and neurodegeneration (Boschert et al. 1999; Buttini et al. 1999, 2002), promote neurite outgrowth (Nathan et al. 2002), or synaptogensis and memory (Levi et al. 2003).”
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“However, other studies have demonstrated that ApoE−/− mice show decreased cholinergic function compared to WT mice (Gordon et al. 1995; Chapman and Michaelson 1998; Kleifeld et al. 1998; Buttini et al. 2002).”
ResultThe effects of the apoE4 genotype on the developing mouse retina
Maharshak, I., Salomon‐Zimri, S., Antes, R., Liraz, O., Nisgav, Y., Livnat, T., Weinberger, D., Colton, C. A., Solomon, A., & Michaelson, D. M. (2015) · Experimental Eye Research · doi:10.1016/j.exer.2015.11.001 · Cited by 9
Retinal manifestations and their diagnostic significance in Alzheimer's disease
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Metadata
- Authors
- Buttini, M., Yu, G.-Q., Shockley, K., Huang, Y., Jones, B., Masliah, E., Mallory, M., Yeo, T., Longo, F. M., & Mucke, L.
- Affiliations
- Gladstone Institutes (US)
- University of California San Diego (US)
- San Francisco VA Medical Center (US)
- Venue
- The Journal of Neuroscience
- Publisher
- Society for Neuroscience
- Published
- 2002-12-15
- Volume
- 22
- Issue
- 24
- Pages
- 10539-10548
- ISSN
- 0270-6474 (ISSN-L)
- 1529-2401
- PMC
- PMC6758409
- OpenAlex
- W2100295360
- Cited by
- 183
- References
- 112
- Citations by year
- 2025: 5 · 2023: 1 · 2022: 2 · 2021: 1 · 2020: 8 · 2019: 6 · 2018: 4 · 2017: 5 · 2016: 2 · 2015: 9 · 2014: 2 · 2013: 9 · 2012: 9
- FWCI
- 8.98
- Type
- journal article
- Language
- en
- Open access
- hybrid
- doi.org
- Licence
- public-domain
- Locations
- Journal of Neuroscience (publishedVersion, public-domain)
- PubMed Central (publishedVersion)
- PubMed (publishedVersion)
- Funders
- Alzheimer's Association
- National Institutes of Health (AG11385)
- National Institute on Aging (AG-11385, R37AG011385, R01AG011385)
- National Cancer Institute (R01CA094141)
- National Institute of Neurological Disorders and Stroke (NS41787, R01NS041787)
- Topics
- Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › Alzheimer's disease research and treatments
- Health Sciences › Medicine › Psychiatry and Mental health › Dementia and Cognitive Impairment Research
- Life Sciences › Neuroscience › Neurology › Neuroinflammation and Neurodegeneration Mechanisms
- Keywords
- apolipoprotein E, APOE ε4, APOE3, Alzheimer's disease, amyloid-beta, amyloid plaques, synaptic deficits, cholinergic deficit, choline acetyltransferase, synaptophysin, brain aging, amyloid precursor protein, transgenic mice, hippocampus, neocortex
- MeSH terms
- Age Factors, Alzheimer Disease, Animals, Apolipoproteins E, Brain, Choline O-Acetyltransferase, Cholinergic Fibers, Humans, Immunohistochemistry, Mice, Transgenic, Peptide Fragments, Amyloid beta-Peptides, Amyloid beta-Protein Precursor, Synaptophysin, Presynaptic Terminals, Protein Isoforms, Mice, Apolipoprotein E3, Apolipoprotein E4
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